Platinum-induced lipid reprogramming and tumor immune microenvironment in SCLC

SCLC 中铂诱导的脂质重编程和肿瘤免疫微环境

基本信息

  • 批准号:
    10657660
  • 负责人:
  • 金额:
    $ 35.45万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-07-01 至 2027-06-30
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Small cell lung cancer (SCLC) is the most aggressive subtype of lung cancer with a five-year survival rate of less than 5%. Immune checkpoint inhibitor (ICI) therapy such as anti-PD1/PD-L1 antibodies has demonstrated unprecedented clinical activity in several difficult-to-treat cancers, with durable responses in a subset of patients. Anti-PD-L1 antibodies such as atezolizumab, for example, have been recently received FDA approval as first line treatment in combination with platinum-based chemotherapy for SCLC; however, the efficacy seems modest. The mechanistic basis for the modest efficacy of immune checkpoint inhibitor in SCLC remains unknown but mounting evidence suggests that the immunosuppressive nature of tumor microenvironment dictates the poor efficacy of immunotherapy in SCLC. In addition, the potential impact of platinum-based chemotherapy on anti- tumor immune response may also play an important role in determining the efficacy of immunotherapy. Dendritic cells (DCs) orchestrate the initiation, programming, and regulation of anti-tumor immune responses. Emerging evidence indicates that the tumor microenvironment induces immune dysfunctional tumor-infiltrating DC (TIDC), characterized with both increased intracellular lipid content and mitochondrial respiration. The underlying mechanism, however, remains largely unclear. Here, we found that fatty acids-carrying tumor derived exosomes (TDEs) induce immune dysfunctional DC to promote immune evasion. We also discover that platinum, the front-line treatment for SCLC, further exacerbates TDE-induced DC dysfunction through reprograming of glutamine-lipid metabolism in SCLC. Mechanistically, platinum rewires glutamine metabolism to promote fatty acid synthesis, leading to enrichment of long chain fatty acids in TDEs. As a result, TIDCs uptake TDEs with large amount of fatty acids that activates peroxisome proliferator activated receptor  (PPAR) signaling, leading to aberrant lipid accumulation and elevated FAO activity, which culminates in the induction of immunosuppressive enzyme arginase 1 (Arg1) and consequently dysfunction in TIDCs. Genetic depletion or pharmacologic inhibition of PPAR effectively attenuates TDE-induced DC-based immune dysfunction and enhances the efficacy of immunotherapy. This work uncovers a role for TDE-mediated immune modulation in DCs and reveals that PPARlies at the center of metabolic-immune regulation of DCs, suggesting a potential immunotherapeutic target. As such, targeting PPAR can be exploited to improve anti-cancer immunotherapy. We will test our hypothesis through the following aims: Aim 1: To explore how TDEs activate PPAR and induce Arg1 to drive DC dysfunction. Aim 2: To investigate how platinum rewires glutamine metabolism in SCLC to induce dendritic cell dysfunction and immune evasion. Aim 3: To evaluate the efficacy of Chemo/anti-PD- L1/PPAR inhibitor combination in SCLC.
项目总结

项目成果

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Lingtao Jin其他文献

Lingtao Jin的其他文献

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{{ truncateString('Lingtao Jin', 18)}}的其他基金

The role of platinum-regulated lipid metabolism in tau-related dementia
铂调节的脂质代谢在 tau 相关痴呆中的作用
  • 批准号:
    10713249
  • 财政年份:
    2022
  • 资助金额:
    $ 35.45万
  • 项目类别:
The role of NFIB-MAST1 signaling in mediating adaptive cisplatin resistance in SCLC
NFIB-MAST1信号在介导SCLC适应性顺铂耐药中的作用
  • 批准号:
    10553970
  • 财政年份:
    2022
  • 资助金额:
    $ 35.45万
  • 项目类别:
Platinum-induced lipid reprogramming and tumor immune microenvironment in SCLC
SCLC 中铂诱导的脂质重编程和肿瘤免疫微环境
  • 批准号:
    10419937
  • 财政年份:
    2022
  • 资助金额:
    $ 35.45万
  • 项目类别:
The role of NFIB-MAST1 signaling in mediating adaptive cisplatin resistance in SCLC
NFIB-MAST1信号在介导SCLC适应性顺铂耐药中的作用
  • 批准号:
    10599274
  • 财政年份:
    2022
  • 资助金额:
    $ 35.45万
  • 项目类别:
The functional role of MAST1 in mediating a-synucleinopathies and related dementia
MAST1 在介导 α-突触核蛋白病和相关痴呆中的功能作用
  • 批准号:
    10285549
  • 财政年份:
    2020
  • 资助金额:
    $ 35.45万
  • 项目类别:

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